GLP-1 (Glucagon-Like Peptide-1) is known as an incretin hormone which is secreted from digestive tracts upon ingestion of food to act on the pancreas and stimulate insulin secretion. As a hormone exhibiting a similar action, there is GIP (Gastric Inhibitory Polypeptide or Glucose-dependent Insulinotropic Polypeptide). This incretin effect is suggested to be absent or reduced inpatients with type 2 diabetes, compared with healthy persons, and this is considered as one of causes high blood glucose. For example, it is reported that inpatients with type 2 diabetes, blood GLP-1 level is lowered, while blood GIP level is normal. As a result of administering the incretin hormones to patients with type 2 diabetes, there is no difference upon the insulin secretion-stimulating activity of GLP-1 between the patients and healthy persons, while the insulin secretion-stimulating activity of GIP is significantly lower in the patients than healthy persons. Accordingly, the response of the patients with diabetes to GLP-1 is maintained; thus, a GLP-1 preparation compensating for its shortage can be expected to serve as a medicine for treatment of diabetes.
The action of GLP-1 on insulin secretion is characterized by glucose level dependent that GLP-1 does not stimulate insulin secretion in the blood glucose level of 110 mg/dL or less. That is, Administration of GLP-1 has clinical advantages that lower possibility of hypoglycemia, and suppress the excessive insulin secretion so that the exhaustion of the pancreas is is prevented. While A sulfonylurea, used mainly in treatment of type 2 diabetes, closes ATP-sensitive K+ channels continuously to promote insulin secretion it causes low blood glucose, exhaustion of the pancreas by excessive stimulation of β cells, and secondary failure in administration for a long period of time. Accordingly, the pharmacological characteristics of GLP-1 are very useful and different from those of the conventional medicine for diabetes.
GLP-1 also have the following characteristics: suppression of glucagon secretion, delay of gastric emptying, suppression of stomach acid secretin, action on the brain to suppress appetite, promotion of insulin synthesis in pancreatic β cells and proliferation of pancreatic β cells. Therefore, GLP-1 is considered not only effective for treatment of diabetes by antagonizing the cause of high blood glucose such as hyperglucagonemia in type 2 diabetes, but also effective for treatment of obesity.
However, as GLP-1 is the polypeptide made up of 30 or 31 amino acids, it is digested upon oral ingestion and decomposed by digestive enzyme in the digestive tract, and is thus not absorbed. The administration thereof by intravenous injection or subcutaneous injection of GLP-1 is attempted at present. Further, it is known that GLP-1 undergoes decomposition with dipeptidyl peptidase IV (DPPIV) present in blood or tissues so that the half-life thereof in the living body is as very short as 1 to 2 minutes, thus giving rise to an obstacle to clinical applications.
To solve these problems, some researches and developments have been made. It is attempted to develop, for example, its derivative having an amino acid sequence substituted at position 8 which is hardly degradable to attain a longer half-life (Diabetologia 41: 271-278 (1998) and Biochem 40: 2860-2869 (2001)) and a sustained-release injection showing sustained subcutaneous absorption. An injection of lizard-derived, synthetic Exendin-4 having a GLP-1 like agonistic activity and a long half-life in blood (Am J Physiol 281: E155-E161 (2001)) is also developed. However, an administration route other than via an injection is desired for wide application of GLP-1 as a medicine for diabetes and in consideration of patients' burden and convenience.
As an administration method not using an invasive means such as an injection or a preparation for oral administration, use of a preparation for absorption through mucous membranes in the lung, oral cavity, nasal cavity, vagina, eye, rectum and the like is available. But a peptide such as GLP-1 upon being administered alone, is poor in absorption via a mucous membrane. Accordingly, a polymer such as peptide is formulated together with an absorption promoter. To secure sustained absorption of chemicals, the preparation makes use of a water-soluble or water-swelling binder, and is formulated in the form of film adhering to the skin layer, buccal tablets, ointment or troche. Many absorption promoters or binders have been examined and found to be effective in facilitating administration of chemicals via mucous membranes. However, as the absorption rate, in terms of bioavailability, of GLP-1 in buccal tablets containing 400 μg GLP-1 through a mucous membrane in the human oral cavity reported by Gutniak et al. (“Diabetes Care” 20: 1874-1879 (1997)), even by using the prior art described above, is 7% of the absorption of its intravenous injection or 47% of the absorption of its subcutaneous injection, and its absorptivity is not sufficient.
Dipeptidyl peptidase IV is known as an enzyme degradating of GLP-1, which is widely distributed not only in the kidney, liver, small intestine, salivary gland and various connecting tissues, but also in body fluid such as blood, urine and saliva and in a mucous membrane in the nasal cavity, and also possibly in other mucous membrane tissues.